The present invention relates to new derivatives of amidines, their preparation and their use as medicaments. It relates in particular to the use of said derivatives for preparing a medicament intended to inhibit NO synthases (NOS) and/or monoamine oxydases (MAO).
Taking into account the potential role of NOS and MAO in physiopathology, the new described derivatives corresponding to general formula (I) can produce beneficial or favourable effects in the treatment of pathologies where these two enzymes are involved. In particular the following pathologies are involved.
disorders of the central or peripheral nervous system such as for example neurological diseases where Parkinson""s disease, cerebral or spinal cord traumatisms, cerebral infarction, sub arachnoid hemorrhage, epilepsy, ageing, senile dementia, Alzheimer""s disease, Huntington""s chorea, amyotrophic lateral sclerosis, peripheral neuropathies, pain;
schizophrenia, depressions, psychoses;
disorders of the memory and the humour;
pathologies such as for example migraine;
behavioural disorders, boulimia and anorexia;
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications (in particular impotence linked to diabetes), multiple sclerosis;
addiction to toxic substances;
proliferative and inflammatory pathologies;
and more generally all the pathologies characterized by an excessive production of NOS and/or participation by MAO.
In all of these pathologies, experimental evidence exists which demonstrates the involvement of NOS (J. Med. Chem. (1995) 38, 4343-4362) as well as the involvement of MAO (Goodman and Gilman""s: The pharmacological hosts of therapeutics, 9th ed., 1995, 431-519).
The inventors have already described inhibitors of NO Synthases and their use in previous patents (U.S. Pat. Nos. 5,081,148; 5,360,925). The PCT Patent Application WO 95/05363 describes certain derivatives of amidines and their use as inhibitors of NO synthases. The Applicant has itself described more recently other derivatives of amidines, which inhibit NO synthases and/or trap the reactive oxygen species (ROS for Reactive Oxygen Species) (cf. in particular PCT Patent Applications WO 98/42696 and WO 98/58934).
The Applicant has just now discovered that, surprisingly, the derivatives of amidines corresponding to general formula (I) defined hereafter are inhibitors of NOS and/or MAO.
The compounds of the invention correspond to the general formula (I) 
in which:
R1 and R2 represent, independently, a hydrogen atom or an alkyl, cycloalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, xe2x80x94(CH2)gxe2x80x94Z1R4 or xe2x80x94(CH2)kxe2x80x94COR5 radical,
Z1 representing xe2x80x94Oxe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94Sxe2x80x94 or a bond,
R4 and R6 representing, independently, a hydrogen atom or an alkyl, alkenyl, allenylalkyl, alkynyl, alkoxy or cyanoalkyl radical,
R5 representing an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or NR7R8 radical,
R7 and R8 representing, independently, a hydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl or alkoxy radical,
or R1 and R2 together with the nitrogen atom form a non-aromatic heterocycle with 4 to 8 members, the elements of the chain being chosen from a group comprising xe2x80x94CH(R9)xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, said heterocycle being able to be substituted by one or more substituents xe2x80x94(CH2)kxe2x80x94Z2R11 or xe2x80x94(CH2)kxe2x80x94COR12, said heterocycle being able to be for example an azetidine, a piperazine, a homopiperazine, a 3,5-dioxopiperazine, a piperidine, a pyrrolidine, a morpholine or a thiomorpholine,
Z2 representing xe2x80x94Oxe2x80x94, xe2x80x94NR13xe2x80x94 or xe2x80x94Sxe2x80x94 or a bond,
R11, each time that it occurs, representing independently a hydrogen atom, an alkyl, alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical,
R13, each time that it occurs, representing, independently, a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical,
R12, each time that it occurs, representing an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, or alkoxy or NR14R15 radical,
R14 and R15, each time that they occur, representing, independently, a hydrogen atom or an alkyl, alkoxy, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,
R9 and R10, each time that they occur, representing independently a hydrogen atom, xe2x80x94(CH2)kxe2x80x94Z3R16 or xe2x80x94(CH2)kCOR17,
Z3 representing xe2x80x94Oxe2x80x94, xe2x80x94NR18xe2x80x94, xe2x80x94Sxe2x80x94 or a bond,
R18 representing, independently, a hydrogen atom or an alkyl, alkenyl, allenyl, allenylalkyl, alkynyl, alkoxy or cyanoalkyl radical,
R16, each time that it occurs, representing independently a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical,
R17, each time that it occurs, representing independently an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or NR19R20 radical,
R19 and R20 representing, independently, each time that they occur, a hydrogen atom or an alkyl alkoxy, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical;
X represents a xe2x80x94COxe2x80x94 or xe2x80x94(CH2)mxe2x80x94 radical;
R3 represents a hydrogen atom or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
A represents a linear or branched alkyl radical having 1 to 6 carbon atoms or a carbocyclic or heterocyclic aryl radical with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furane, pyrrole or thiazole radicals, said aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
g, each time that it occurs, representing, independently, an integer from 1 to 6,
m, k and n, each time that they occur, representing, independently, integers from 0 to 6;
it being understood however that, when R3 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, then R1 and R2 do not represent, independently, a hydrogen atom or an alkyl radical, and moreover NR1R2 do not represent one of the non substituted piperidinyl, morpholinyl, pyrrolidinyl groups or the piperazinyl group optionally substituted in position 4 by an alkyl radical containing 1 to 6 carbon atoms.
By alkyl, when it is not specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, when it is not specified otherwise, is meant a monocyclic carbon system containing 3 to 7 carbon atoms. By alkenyl, when it is not specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, when it is not specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By allenyl, is meant the xe2x80x94CHxe2x95x90Cxe2x95x90CH2 radical. By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being called heterocyclic when at least one of the rings which comprise it contains a heteroatom (O, N or S). By heterocycle, is meant a mono- or polycyclic system said system comprising at least one heteroatom chosen from O, N and S and being saturated, partially or totally unsaturated or aromatic. By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) are replaced by a halogen atom.
By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, cyanoalkyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, cyanoalkyl and aralkyl radicals of which the alkyl radical has the meaning indicated previously.
By heterocycle, is meant in particular the thiophene, pyrrole, pyrrolidine, furane, tetrahydrofuran, piperidine, piperazine, quinoline, indoline and indole radicals. By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. Finally, by halogen, is meant the fluorine, chlorine, bromine or iodine atoms.
In certain cases, the compound according to the present invention can contain asymmetrical carbon atoms. As a result, the compounds according to the present invention have two possible enantiomeric forms, i.e. the xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the racemic xe2x80x9cRSxe2x80x9d mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
The invention relates in particular to the products of general formula (I) defined previously, in which, independently, at least one of the following characteristics is found:
R1 representing an alkyl radical and R2 representing one of the alkyl, cycloalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, xe2x80x94(CH2)gxe2x80x94Z1R4 or xe2x80x94(CH2)kxe2x80x94COR5 radicals as defined above;
R1 and R2 together with the nitrogen atom forming a non-aromatic heterocycle with 4 to 8 members, the elements of the chain being chosen from a group comprising xe2x80x94CH(R9)xe2x80x94, xe2x80x94NR10xe2x80x94 and xe2x80x94Oxe2x80x94,
R9 and R10 representing independently a hydrogen atom or a xe2x80x94(CH2)kxe2x80x94Z3R16 or xe2x80x94(CH2)kCOR17 radical,
Z3 representing a bond,
R16 representing independently a hydrogen atom, an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,
R17 representing independently an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical;
n representing 0 or 1;
k representing an integer from 1 to 6;
X representing xe2x80x94(CH2)mxe2x80x94 with m representing 0 or 1.
More preferably, the products of general formula (I) defined previously, such that, independently, at least one of the following characteristics is found:
R1 representing an alkyl radical and R2 representing one of the alkyl, alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radicals;
R1 and R2 together with the nitrogen atom form a non-aromatic heterocycle with 4 to 8 members, the elements of the chain being chosen from a group comprising xe2x80x94CH(R9)xe2x80x94 and xe2x80x94NR10xe2x80x94,
R9 and R10 representing independently a hydrogen atom or a xe2x80x94(CH2)kxe2x80x94Z3R16 radical,
Z3 representing a bond,
R16 representing independently a hydrogen atom or an alkyl, alkynyl or cyanoalkyl radical;
n representing 0 or 1;
k representing an integer from 1 to 3;
X representing xe2x80x94(CH2)mxe2x80x94 with m representing 0 or 1;
The particularly preferred products of general formula (I) are:
Nxe2x80x2-(4-{[methyl-(2-propynyl)amino]methyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{[methyl(cyanomethyl)amino]methyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{[methyl(propyl)amino]methyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{[methyl(3-cyanoethyl)amino]methyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{[methyl(4-pentynyl)amino]methyl}phenyl)-2-thiophenecarboximidamide;
and the salts of the latter.
Finally, Nxe2x80x2-(4-{[methyl-(2-propynyl)amino]methyl}phenyl)-2-thiophene carboximidamide or the salts of the latter are particularly preferred.
The invention also relates, as medicaments, to the compounds of general formula (I) or their pharmaceutically acceptable salts. In addition, a subject of the invention is the pharmaceutical compositions containing, as active ingredient, a compound of general formula (I) or a pharmaceutically acceptable salt of a compound of general formula (I), as well as the use of the compounds of general formula (I) for preparing a medicament intended to inhibit NO synthases and/or monoamine oxydases, in particular monoamine oxydase B.
In particular, the compounds of general formula (I) can be used for preparing a medicament intended to treat one of the following disorders or one of the following diseases: Parkinson""s disease, senile dementia, Alzheimer""s disease, Huntington""s chorea, amyotrophic lateral sclerosis, schizophrenia, depression, psychoses.
By pharmaceutically acceptable salt, is meant in particular the addition salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate, and nitrate or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, and stearate. Also included in the scope of the present invention, when they can be used, are the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cSalt selection for basic drugsxe2x80x9d, Int. J. Pharm. (1986), 33, 201-217.
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, similarly their mixtures, in varying proportions, in water.
The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg to 10 g according to the type of active compound used.
In accordance with the invention, the compounds of general formula (I) can be prepared by the processes described below.
The compounds of general formula (I) can be prepared from the intermediates of general formula (II) according to Diagram 1 where A, X, R1, R2, R3 and n are as defined above and Gp is a protective group of carbamate type. 
The derivatives of anilines of general formula (II), can be condensed with the compounds of general formula (III), in which L represents a parting group (an alkoxy, alkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical), in order to produce the final compounds of general formula (I) of substituted amidine type (cf. Diagram 1). For example, for A=thiophene, the derivatives of general formula (II) can be condensed with S-methylthiophene thiocarboxamide hydroiodide, prepared according to a method in the literature (Ann. Chim. (1962), 7, 303-337). The condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature preferably comprised between 50 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight.
In the case where A is an amine, the final compounds of general formula (I) are guanidines. These can be prepared, for example, by the condensation of the amines of general formula (II) with the derivatives of general formula (IV) or (IVxe2x80x2). The reagents of general formula (IV), in which L represents, for example, a pyrazole ring, are condensed with the anilines of general formula (II) according to conditions described in the literature (J. Org. Chem. (1992) 57, 2497-2502). The operation is carried out similarly for the reagents of general formula (IVxe2x80x2) in which L represents, for example, a pyrazole ring and Gp the tBuOCO group (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or when L represents the xe2x80x94Nxe2x80x94SO2xe2x80x94CF3 group and Gp the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805). During the last stage of the synthesis, the deprotection of the guanidine function is carried out in the presence of a strong acid such as for example trifluoroacetic acid.
The intermediates of general formula (II), are obtained, for example, from the reduction of a precursor of nitro type, as illustrated in synthesis Diagram 2 below.
Reduction of the Precursors of Nitro Type:
The reduction of the nitro function of the intermediates of general formula (V), Diagram 2, in which R1, R2, R3, X and n and are as defined above, is generally carried out by catalytic hydrogenation, in ethanol, in the presence of Pd/C, except in the case of molecules which are sensitive to these conditions where the nitro group is selectively reduced, for example, while heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J. Heterocyclic Chem. 1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842) in the presence of SnCl2/Zn (Synthesis. (1996), 9, 1076-1078) or using NaBH4xe2x80x94BiCl3 (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such as ethanol, or then by using Rancy Ni with hydrazine hydrate added to it (Monatshefte fiir Chemie, (1995), 126, 725-732). 
Syntheses of the Carboxamides:
The carboxamides of general formula (V), Diagram 3, in which R1, R2, R3, m and n are as defined above, are prepared by condensation of the acids of general formula (VI) with the amines of general formula (VII) (Diagram 3) or of the acids of the general formula (VIII) with of the amines of general formula (IX) (Diagram 3a) under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in particular in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)). 
Synthesis of the Amines of General Formula (V):
The amines of general formula (V), Diagram 4, in which R1, R2, R3, m and n as defined above, can be prepared in a single stage by condensation of the amines of general formula (VII) with the halogenated derivatives of general formula (X) (Hal represents a halogen atom) in the presence of a base such as, for example, K2CO3 and/or triethylamine, in a solvent such as, for example, acetonitrile. 
When R1, R2, R3, m and n are as defined above, the amines of general formula (V) can also be prepared from the halogenated derivatives of formula (XI) (Hal represents a halogen atom) and the amines of general formula (IX), Diagram 5, in the presence of a base such as, for example, K2CO3 and/or triethylamine, in a solvent such as, for example, acetonitrile. 
Synthesis of the Amines by Reducing Amination:
The amines of general formula (V), Diagram 6, in which R1, R2, R3, m and n are as defined above, can be prepared by condensation of an aldehyde of general formula (XII) with an amine of general formula (VII) in a reducing medium. The reaction takes place in an alcoholic solvent such as, for example, methanol in the presence of a pulverulent 4 xc3x85 molecular sieve, activated beforehand, and of a reducing agent such as, for example, NaBH4 or NaBH3CN. 
The amines of general formula (V), Diagram 7, in which R1, R2, R3 and n are as defined above, can also be prepared by condensation of an amine of general formula (IX) with an aldehyde of general formula (XIII) in a reducing medium under the conditions described previously. 
Unless otherwise defined, all the technical and scientific terms used here have the same meanings as those generally understood by an ordinary specialist in the field to which this invention belongs. Similarly, all the publications, patent applications, all patents and all other references mentioned here are incorporated by way of reference.
The following examples are presented in order to illustrate the above procedures and should in no event by considered as a limit to the scope of the invention.